{"gene":"ZYX","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2002,"finding":"C. elegans ZYX-1 (zyxin orthologue) binds GLH germline RNA helicases, as demonstrated by yeast two-hybrid screening and independent GST pull-down assays. ZYX-1 is a LIM-domain protein most similar to vertebrate zyxin.","method":"Yeast two-hybrid screen; GST pull-down assay","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed by two orthogonal methods (Y2H + GST pull-down), single lab","pmids":["12435362"],"is_preprint":false},{"year":2007,"finding":"C. elegans ZYX-1 interacts with DYC-1 (a dystrophin-associated protein) at dense bodies in muscle. The interaction was mapped to a conserved 19-amino-acid sequence in DYC-1 that is sufficient for dense-body targeting, placing ZYX-1 at the C. elegans sarcomeric adhesion structure.","method":"Yeast two-hybrid assay; immunolocalization; domain-mapping experiments","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus localization with domain mapping, single lab","pmids":["18094057"],"is_preprint":false},{"year":2013,"finding":"C. elegans ZYX-1 localizes to dense bodies/Z-discs and M-lines in striated body-wall muscle and shuttles into the nucleus, suggesting a signal-transduction role. ZYX-1 interacts with DEB-1/vinculin and ATN-1/α-actinin by yeast two-hybrid. Localization and dynamics at dense bodies depend on ATN-1. FRAP reveals high mobility of ZYX-1 at these structures, consistent with a peripheral, dynamic association. Two isoforms (ZYX-1a and ZYX-1b) play distinct roles in dystrophin-dependent muscle degeneration.","method":"Yeast two-hybrid; fluorescence microscopy; FRAP; isoform-specific analysis; C. elegans genetics","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, live imaging, FRAP, genetic isoform analysis) in a single rigorous study","pmids":["23427270"],"is_preprint":false},{"year":2014,"finding":"C. elegans ZYX-1 maintains mechanosensory synapse integrity against locomotion-induced mechanical forces in vivo. The synapse-stabilizing activity is mediated by the C-terminal LIM domains alone; the N-terminal domain (which binds α-actinin and ENA-VASP) is dispensable for this function.","method":"C. elegans genetics (loss-of-function mutants); locomotion suppression epistasis; isoform rescue experiments","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, isoform-specific rescue, and locomotion suppression experiments provide multiple orthogonal lines of evidence in a single focused study","pmids":["25252943"],"is_preprint":false},{"year":2020,"finding":"ZYX promotes invasion of human glioblastoma cells; ZYX loss reduces invasion. RNA-seq and mass spectrometry identified STMN1 as a downstream target whose mRNA and protein levels are positively regulated by ZYX. STMN1 rescues the invasion deficit caused by ZYX knockdown, placing ZYX upstream of STMN1 in a pro-invasive axis.","method":"ZYX knockdown/overexpression; RNA-seq; mass spectrometry; STMN1 rescue experiments; in vitro invasion assays; in vivo experiments","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (RNA-seq, proteomics, rescue assay) in single lab; pathway placement by epistasis","pmids":["31949244"],"is_preprint":false},{"year":2020,"finding":"A peptide fragment of ZYX (ZYX36-58) inhibits invasion and migration and promotes apoptosis of ovarian cancer cells. Mechanistically, ZYX36-58 binds and up-regulates the antiangiogenic/tumor-suppressive protein thrombospondin-1 (TSP1), as shown by peptide pull-down assay.","method":"Peptide pull-down assay; CCK8, transwell, wound-healing, and flow cytometry assays; RNA-seq","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down plus multiple functional assays, single lab","pmids":["32953725"],"is_preprint":false},{"year":2022,"finding":"C. elegans ZYX-1/Zyxin is recruited to apical junctions in dorsal and ventral epidermal cells during embryonic elongation when junctions are under tension. Its LCR region is recruited to stress fiber strain sites in cultured vertebrate cells. Loss of ZYX-1 causes junctional F-actin defects and enhances morphogenetic defects in cadherin/catenin complex hypomorphs, establishing ZYX-1 as part of a tension-sensitive system that stabilizes junctional actin during morphogenesis.","method":"C. elegans genetics; fluorescence imaging; genetic epistasis with CCC hypomorphs; vertebrate cell culture SFSS recruitment assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo genetics, imaging, epistasis, vertebrate cell assay) across two organisms in a single study","pmids":["36384139"],"is_preprint":false},{"year":2024,"finding":"Endothelial zyxin acts as a mechanosensor under oscillatory shear stress (OSS) and promotes YAP nuclear translocation and endothelial inflammation. Mechanistically, zyxin interacts with 14-3-3β and inhibits 14-3-3β-facilitated phosphorylation of YAP at Serine 127, thereby reducing cytoplasmic retention of YAP and allowing nuclear YAP-driven inflammatory gene expression. EC-specific zyxin knockout in ApoE−/− mice reduces OSS-induced atherosclerosis.","method":"Endothelial cell-specific knockout mouse model (ZyxiniECKO ApoE−/−); disturbed-flow in vitro system; mechanistic co-immunoprecipitation/interaction studies with 14-3-3β and YAP; phosphorylation analysis","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model plus mechanistic interaction studies, single lab, preprint not peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"ZYX acts downstream of ITGB1 in hepatocellular carcinoma cells. ITGB1 knockdown suppresses the FAK/AKT pathway; ZYX knockdown phenocopies this and also suppresses the FAK/AKT pathway. ZYX knockdown inhibits the growth-promoting effect of ITGB1 overexpression, while ZYX knockdown has no effect on ITGB1 expression, placing ZYX downstream of ITGB1 in the ITGB1/ZYX/FAK/AKT axis governing EMT and apoptosis.","method":"siRNA knockdown; overexpression rescue; in vivo xenograft model; Western blot for pathway components","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by knockdown/overexpression with pathway readout, single lab","pmids":["39143566"],"is_preprint":false},{"year":2025,"finding":"Zyxin restricts viral envelope fusion and entry broadly across multiple virus families (HSV-1, PRV, paramyxovirus, rhabdovirus). Zyxin-KO cells show enhanced cell-cell fusion and larger viral plaques. Bulk RNA-seq of zyxin-KO cells identified altered expression of genes related to membrane potential, extracellular matrix organization, and MAPK cascade regulation, suggesting zyxin influences membrane properties relevant to viral fusion.","method":"CRISPR/Cas9 knockout; quantitative cell-cell fusion assay; plaque assay; bulk RNA-seq","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple virus families tested and quantitative fusion assay; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Zyxin and VASP cooperate to assemble dense, uniformly polar actin bundles at focal adhesions with barbed ends oriented toward the cell edge. CRISPR/Cas9 knockout of zyxin and/or VASP alters FA morphology and dynamics. Cryo-ET resolves the polarity of actin filaments at FAs; the tropomyosin-decorated dorsal actin layer is unaffected by zyxin/VASP loss, revealing layered FA architecture.","method":"CRISPR/Cas9 knockout; cryo-electron tomography; live-cell imaging of FA dynamics","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-ET structural analysis combined with genetic KO, single lab, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"RAD51-AS1 lncRNA activates ZYX transcription via the HNRNPC/RARA axis in prostate cancer cells. RAD51-AS1 recruits HNRNPC to bind pre-RARA mRNA, positively modulating RARA expression; RARA in turn activates ZYX transcription. This pathway suppresses PCa cell migration and invasion, and rescue assays confirm RAD51-AS1 acts through ZYX.","method":"RT-qPCR; RIP/RNA binding assays; transcription reporter/ChIP-type analysis; knockdown/overexpression rescue assays; functional migration/invasion assays","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis established by rescue assay with multiple molecular mechanism assays, single lab","pmids":["41134509"],"is_preprint":false},{"year":2025,"finding":"Coumestrol (CMS) binds ZYX directly (molecular docking supported by cell biology), down-regulates ZYX expression, and reduces TGF-β/SMAD pathway activity, thereby inhibiting ferroptosis in pancreatic acinar cells. ZYX overexpression counteracts the inhibitory effects of CMS on TGF-β/SMAD signaling and ferroptosis, placing ZYX upstream of TGF-β/SMAD in acinar cell ferroptosis.","method":"Molecular docking; WGCNA/network pharmacology; ZYX overexpression epistasis; in vivo caerulein-induced AP mouse model; ferroptosis assays","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — molecular docking is computational; functional epistasis (ZYX OE rescue) provides some experimental support but limited orthogonal mechanistic validation, single lab","pmids":["40414075"],"is_preprint":false}],"current_model":"Zyxin (ZYX) is a LIM-domain focal adhesion adaptor that bridges integrin-based adhesion receptors with the actin cytoskeleton; it localizes dynamically to focal adhesions, stress fibers, and (in muscle/nematode) dense bodies/Z-discs, where—together with VASP—it assembles uniformly polar actin bundles, stabilizes junctional and synaptic actin networks under mechanical tension, and transduces force signals via a zyxin–14-3-3β–YAP axis to drive inflammatory gene expression; it also acts as a broad antiviral factor antagonizing envelope fusion, and functions as a transcriptionally regulated node (upstream of STMN1, downstream of ITGB1) in cancer cell invasion."},"narrative":{"mechanistic_narrative":"Zyxin (ZYX) is a LIM-domain cytoskeletal adaptor that localizes to mechanically loaded adhesion structures and stabilizes actin networks under tension, while also shuttling to the nucleus to couple mechanical input to gene expression [PMID:23427270, PMID:36384139]. At focal adhesions it cooperates with VASP to assemble dense, uniformly polar actin bundles whose barbed ends orient toward the cell edge, defining a distinct layer of focal-adhesion architecture. In striated muscle its orthologue ZYX-1 concentrates at dense bodies/Z-discs and M-lines through interactions with α-actinin (ATN-1), vinculin (DEB-1), and the dystrophin-associated protein DYC-1, with localization dependent on α-actinin [PMID:18094057, PMID:23427270]. Its tension-sensitive recruitment stabilizes junctional and synaptic F-actin against mechanical force during morphogenesis and at mechanosensory synapses, a function residing in the C-terminal LIM domains [PMID:25252943, PMID:36384139]. Under oscillatory shear stress, endothelial zyxin acts as a mechanosensor that binds 14-3-3β to inhibit YAP Ser127 phosphorylation, promoting nuclear YAP translocation and inflammatory gene expression that drives atherosclerosis. Zyxin is embedded in cancer signaling as a transcriptionally regulated node acting downstream of ITGB1 through the FAK/AKT axis and upstream of STMN1 in tumor cell invasion [PMID:31949244, PMID:39143566]. It also broadly restricts viral envelope fusion and entry across multiple virus families.","teleology":[{"year":2002,"claim":"Established the first molecular partners of a zyxin orthologue, linking the LIM-domain protein ZYX-1 to germline RNA helicases and hinting at functions beyond adhesion.","evidence":"Yeast two-hybrid screen and GST pull-down in C. elegans","pmids":["12435362"],"confidence":"Medium","gaps":["Functional consequence of the GLH interaction not defined","Relevance to vertebrate zyxin unknown"]},{"year":2007,"claim":"Placed ZYX-1 at the sarcomeric adhesion structure by mapping a short DYC-1 sequence sufficient for dense-body targeting, connecting zyxin to dystrophin-associated muscle architecture.","evidence":"Yeast two-hybrid, immunolocalization, and domain mapping in C. elegans muscle","pmids":["18094057"],"confidence":"Medium","gaps":["Mechanical or signaling role at dense bodies not tested","No vertebrate confirmation"]},{"year":2013,"claim":"Defined ZYX-1 as a dynamic, peripherally associated component of muscle dense bodies and Z-discs that depends on α-actinin and shuttles to the nucleus, suggesting a mechanotransduction role.","evidence":"Yeast two-hybrid, live imaging, FRAP, and isoform-specific genetics in C. elegans","pmids":["23427270"],"confidence":"High","gaps":["Nuclear targets of shuttled ZYX-1 unidentified","Mechanism distinguishing the two isoforms incomplete"]},{"year":2014,"claim":"Showed that zyxin stabilizes mechanosensory synapses against locomotion-induced force and localized this activity to the C-terminal LIM domains, separating force-stabilization from actin/α-actinin binding.","evidence":"Loss-of-function genetics, epistasis, and isoform rescue in C. elegans","pmids":["25252943"],"confidence":"High","gaps":["Molecular partners of the LIM domains at synapses not identified","How LIM domains sense force not resolved"]},{"year":2020,"claim":"Identified ZYX as a pro-invasive node in cancer, placing it upstream of STMN1 and demonstrating a tumor-suppressive ZYX-derived peptide that engages TSP1, revealing both full-length and fragment-level functions.","evidence":"Knockdown/overexpression with RNA-seq, proteomics, and rescue in glioblastoma; peptide pull-down and functional assays in ovarian cancer","pmids":["31949244","32953725"],"confidence":"Medium","gaps":["Mechanism by which ZYX regulates STMN1 levels unknown","Physiological relevance of ZYX36-58 peptide unclear"]},{"year":2022,"claim":"Demonstrated tension-dependent recruitment of zyxin to apical junctions and stress-fiber strain sites, establishing it as part of a force-sensitive system stabilizing junctional actin during morphogenesis.","evidence":"C. elegans genetics, imaging, epistasis with cadherin/catenin hypomorphs, and vertebrate stress-fiber strain-site recruitment assay","pmids":["36384139"],"confidence":"High","gaps":["The force-sensing element within zyxin not molecularly defined","Link between junctional and focal-adhesion roles unresolved"]},{"year":2024,"claim":"Connected zyxin mechanosensing to transcription by showing it binds 14-3-3β to relieve YAP Ser127 phosphorylation, driving nuclear YAP and endothelial inflammation in atherosclerosis.","evidence":"Endothelial-specific knockout ApoE−/− mouse, disturbed-flow system, and co-IP/phosphorylation studies (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct binding of zyxin to 14-3-3β versus indirect effect not fully distinguished"]},{"year":2024,"claim":"Positioned ZYX within the ITGB1/FAK/AKT signaling axis, showing it acts downstream of integrin β1 to drive EMT and suppress apoptosis in hepatocellular carcinoma.","evidence":"siRNA knockdown, overexpression rescue, xenograft, and pathway Western blots","pmids":["39143566"],"confidence":"Medium","gaps":["Direct biochemical link between ZYX and FAK/AKT not shown","Whether effect requires zyxin's cytoskeletal localization untested"]},{"year":2025,"claim":"Resolved the structural output of zyxin-VASP cooperation at focal adhesions, showing assembly of uniformly polar actin bundles and a layered focal-adhesion architecture.","evidence":"CRISPR/Cas9 knockout, cryo-electron tomography, and live-cell imaging (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Order of zyxin and VASP recruitment to nascent bundles unresolved"]},{"year":2025,"claim":"Revealed an unexpected broad antiviral function in which zyxin restricts viral envelope fusion and entry, potentially via effects on membrane properties.","evidence":"CRISPR/Cas9 knockout, cell-cell fusion and plaque assays, and bulk RNA-seq (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct molecular mechanism linking zyxin to membrane fusion undefined"]},{"year":2025,"claim":"Extended ZYX's regulatory range as a transcriptionally controlled node, identifying lncRNA/HNRNPC/RARA-driven activation of ZYX that suppresses prostate cancer invasion and a TGF-β/SMAD-coupled role in acinar cell ferroptosis.","evidence":"RIP, reporter/ChIP-type analysis, and rescue in prostate cancer; molecular docking and overexpression epistasis in a pancreatitis mouse model","pmids":["41134509","40414075"],"confidence":"Medium","gaps":["Ferroptosis link rests partly on computational docking","Apparently opposite invasion effects across cancer contexts unreconciled"]},{"year":null,"claim":"How zyxin's mechanosensitive LIM domains physically sense force and how this single adaptor coordinates its adhesion, transcriptional, antiviral, and context-dependent cancer roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of force-induced conformational change","Unifying mechanism across diverse functions not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,10]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,6,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[6,10]}],"complexes":["focal adhesion","dense body/Z-disc"],"partners":["VASP","ATN-1/ALPHA-ACTININ","DEB-1/VINCULIN","DYC-1","14-3-3BETA","YAP","GLH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15942","full_name":"Zyxin","aliases":["Zyxin-2"],"length_aa":572,"mass_kda":61.3,"function":"Adhesion plaque protein. Binds alpha-actinin and the CRP protein. Important for targeting TES and ENA/VASP family members to focal adhesions and for the formation of actin-rich structures. May be a component of a signal transduction pathway that mediates adhesion-stimulated changes in gene expression (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Nucleus; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q15942/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZYX","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000159840","cell_line_id":"CID000885","localizations":[{"compartment":"cell_contact","grade":3}],"interactors":[{"gene":"ENAH","stoichiometry":4.0},{"gene":"ATP1A1","stoichiometry":0.2},{"gene":"AZGP1","stoichiometry":0.2},{"gene":"SERPINB3;SERPINB4","stoichiometry":0.2},{"gene":"CCAR1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000885","total_profiled":1310},"omim":[{"mim_id":"620941","title":"SYNAPTOPODIN 2; SYNPO2","url":"https://www.omim.org/entry/620941"},{"mim_id":"619683","title":"B-BOX- AND SPRY DOMAIN-CONTAINING PROTEIN; BSPRY","url":"https://www.omim.org/entry/619683"},{"mim_id":"618649","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 1; HECTD1","url":"https://www.omim.org/entry/618649"},{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"609061","title":"ENAH ACTIN REGULATOR; ENAH","url":"https://www.omim.org/entry/609061"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZYX"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q15942","domains":[{"cath_id":"2.10.110.10","chopping":"382-441","consensus_level":"medium","plddt":88.0588,"start":382,"end":441},{"cath_id":"2.10.110.10","chopping":"443-501","consensus_level":"medium","plddt":89.6593,"start":443,"end":501},{"cath_id":"2.10.110.10","chopping":"502-572","consensus_level":"medium","plddt":87.5601,"start":502,"end":572}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15942","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15942-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15942-F1-predicted_aligned_error_v6.png","plddt_mean":63.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZYX","jax_strain_url":"https://www.jax.org/strain/search?query=ZYX"},"sequence":{"accession":"Q15942","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15942.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15942/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15942"}},"corpus_meta":[{"pmid":"12435362","id":"PMC_12435362","title":"The GLH proteins, Caenorhabditis elegans P granule components, associate with CSN-5 and KGB-1, proteins necessary for fertility, and with ZYX-1, a predicted cytoskeletal protein.","date":"2002","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/12435362","citation_count":60,"is_preprint":false},{"pmid":"38387395","id":"PMC_38387395","title":"Anti-diabetic and anti-inflammatory indole diterpenes from the marine-derived fungus Penicillium sp. ZYX-Z-143.","date":"2024","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38387395","citation_count":23,"is_preprint":false},{"pmid":"31949244","id":"PMC_31949244","title":"Zyxin (ZYX) promotes invasion and acts as a biomarker for aggressive phenotypes of human glioblastoma multiforme.","date":"2020","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31949244","citation_count":21,"is_preprint":false},{"pmid":"23427270","id":"PMC_23427270","title":"ZYX-1, the unique zyxin protein of Caenorhabditis elegans, is involved in dystrophin-dependent muscle degeneration.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23427270","citation_count":20,"is_preprint":false},{"pmid":"18094057","id":"PMC_18094057","title":"DYC-1, a protein functionally linked to dystrophin in Caenorhabditis elegans is associated with the dense body, where it interacts with the muscle LIM domain protein ZYX-1.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18094057","citation_count":19,"is_preprint":false},{"pmid":"25252943","id":"PMC_25252943","title":"The conserved LIM domain-containing focal adhesion protein ZYX-1 regulates synapse maintenance in Caenorhabditis elegans.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25252943","citation_count":19,"is_preprint":false},{"pmid":"21920000","id":"PMC_21920000","title":"QS-ZYX-1-61 induces apoptosis through topoisomerase II in human non-small-cell lung cancer A549 cells.","date":"2011","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/21920000","citation_count":14,"is_preprint":false},{"pmid":"20374769","id":"PMC_20374769","title":"Association of ZYX polymorphisms with carcass and meat quality traits in commercial pigs.","date":"2009","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/20374769","citation_count":9,"is_preprint":false},{"pmid":"36384139","id":"PMC_36384139","title":"TES-1/Tes and ZYX-1/Zyxin protect junctional actin networks under tension during epidermal morphogenesis in the C. elegans embryo.","date":"2022","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/36384139","citation_count":7,"is_preprint":false},{"pmid":"32953725","id":"PMC_32953725","title":"Peptidome characterization of ovarian cancer serum and the identification of tumor suppressive peptide ZYX36-58.","date":"2020","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32953725","citation_count":6,"is_preprint":false},{"pmid":"39225394","id":"PMC_39225394","title":"Persteroid, a new steroid from the marine-derived fungus Penicillium sp. ZYX-Z-143.","date":"2024","source":"Natural product research","url":"https://pubmed.ncbi.nlm.nih.gov/39225394","citation_count":5,"is_preprint":false},{"pmid":"39143566","id":"PMC_39143566","title":"Does rAj-Tspin, a novel peptide from A. japonicus, exert antihepatocellular carcinoma effects via the ITGB1/ZYX/FAK/AKT signaling pathway?","date":"2024","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/39143566","citation_count":1,"is_preprint":false},{"pmid":"40414075","id":"PMC_40414075","title":"Network pharmacology analysis reveals that coumestrol targets ZYX to inhibit ferroptosis and alleviate acute pancreatitis.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40414075","citation_count":0,"is_preprint":false},{"pmid":"41134509","id":"PMC_41134509","title":"RAD51-AS1 inhibits the migration and invasion of prostate cancer cells by up-regulating RARA to activate ZYX transcription.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41134509","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.03.680228","title":"Zyxin Restricts Viral Fusion and Entry across Multiple Virus Families","date":"2025-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.03.680228","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.06.673321","title":"Endothelial tight junctions and cell-matrix adhesions reciprocally control blood-brain barrier integrity","date":"2025-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.06.673321","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.08.681099","title":"VASP regulates the polar organization of adhesion-associated actin filaments","date":"2025-10-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.08.681099","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.21.619550","title":"Deletion of Zyxin Reduces Endothelial Inflammation and Mitigates Atherosclerosis","date":"2024-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.21.619550","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11195,"output_tokens":3464,"usd":0.042772,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11176,"output_tokens":3758,"usd":0.074915,"stage2_stop_reason":"end_turn"},"total_usd":0.117687,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"C. elegans ZYX-1 (zyxin orthologue) binds GLH germline RNA helicases, as demonstrated by yeast two-hybrid screening and independent GST pull-down assays. ZYX-1 is a LIM-domain protein most similar to vertebrate zyxin.\",\n      \"method\": \"Yeast two-hybrid screen; GST pull-down assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed by two orthogonal methods (Y2H + GST pull-down), single lab\",\n      \"pmids\": [\"12435362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans ZYX-1 interacts with DYC-1 (a dystrophin-associated protein) at dense bodies in muscle. The interaction was mapped to a conserved 19-amino-acid sequence in DYC-1 that is sufficient for dense-body targeting, placing ZYX-1 at the C. elegans sarcomeric adhesion structure.\",\n      \"method\": \"Yeast two-hybrid assay; immunolocalization; domain-mapping experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus localization with domain mapping, single lab\",\n      \"pmids\": [\"18094057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans ZYX-1 localizes to dense bodies/Z-discs and M-lines in striated body-wall muscle and shuttles into the nucleus, suggesting a signal-transduction role. ZYX-1 interacts with DEB-1/vinculin and ATN-1/α-actinin by yeast two-hybrid. Localization and dynamics at dense bodies depend on ATN-1. FRAP reveals high mobility of ZYX-1 at these structures, consistent with a peripheral, dynamic association. Two isoforms (ZYX-1a and ZYX-1b) play distinct roles in dystrophin-dependent muscle degeneration.\",\n      \"method\": \"Yeast two-hybrid; fluorescence microscopy; FRAP; isoform-specific analysis; C. elegans genetics\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, live imaging, FRAP, genetic isoform analysis) in a single rigorous study\",\n      \"pmids\": [\"23427270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C. elegans ZYX-1 maintains mechanosensory synapse integrity against locomotion-induced mechanical forces in vivo. The synapse-stabilizing activity is mediated by the C-terminal LIM domains alone; the N-terminal domain (which binds α-actinin and ENA-VASP) is dispensable for this function.\",\n      \"method\": \"C. elegans genetics (loss-of-function mutants); locomotion suppression epistasis; isoform rescue experiments\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, isoform-specific rescue, and locomotion suppression experiments provide multiple orthogonal lines of evidence in a single focused study\",\n      \"pmids\": [\"25252943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZYX promotes invasion of human glioblastoma cells; ZYX loss reduces invasion. RNA-seq and mass spectrometry identified STMN1 as a downstream target whose mRNA and protein levels are positively regulated by ZYX. STMN1 rescues the invasion deficit caused by ZYX knockdown, placing ZYX upstream of STMN1 in a pro-invasive axis.\",\n      \"method\": \"ZYX knockdown/overexpression; RNA-seq; mass spectrometry; STMN1 rescue experiments; in vitro invasion assays; in vivo experiments\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (RNA-seq, proteomics, rescue assay) in single lab; pathway placement by epistasis\",\n      \"pmids\": [\"31949244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A peptide fragment of ZYX (ZYX36-58) inhibits invasion and migration and promotes apoptosis of ovarian cancer cells. Mechanistically, ZYX36-58 binds and up-regulates the antiangiogenic/tumor-suppressive protein thrombospondin-1 (TSP1), as shown by peptide pull-down assay.\",\n      \"method\": \"Peptide pull-down assay; CCK8, transwell, wound-healing, and flow cytometry assays; RNA-seq\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down plus multiple functional assays, single lab\",\n      \"pmids\": [\"32953725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C. elegans ZYX-1/Zyxin is recruited to apical junctions in dorsal and ventral epidermal cells during embryonic elongation when junctions are under tension. Its LCR region is recruited to stress fiber strain sites in cultured vertebrate cells. Loss of ZYX-1 causes junctional F-actin defects and enhances morphogenetic defects in cadherin/catenin complex hypomorphs, establishing ZYX-1 as part of a tension-sensitive system that stabilizes junctional actin during morphogenesis.\",\n      \"method\": \"C. elegans genetics; fluorescence imaging; genetic epistasis with CCC hypomorphs; vertebrate cell culture SFSS recruitment assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo genetics, imaging, epistasis, vertebrate cell assay) across two organisms in a single study\",\n      \"pmids\": [\"36384139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endothelial zyxin acts as a mechanosensor under oscillatory shear stress (OSS) and promotes YAP nuclear translocation and endothelial inflammation. Mechanistically, zyxin interacts with 14-3-3β and inhibits 14-3-3β-facilitated phosphorylation of YAP at Serine 127, thereby reducing cytoplasmic retention of YAP and allowing nuclear YAP-driven inflammatory gene expression. EC-specific zyxin knockout in ApoE−/− mice reduces OSS-induced atherosclerosis.\",\n      \"method\": \"Endothelial cell-specific knockout mouse model (ZyxiniECKO ApoE−/−); disturbed-flow in vitro system; mechanistic co-immunoprecipitation/interaction studies with 14-3-3β and YAP; phosphorylation analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model plus mechanistic interaction studies, single lab, preprint not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZYX acts downstream of ITGB1 in hepatocellular carcinoma cells. ITGB1 knockdown suppresses the FAK/AKT pathway; ZYX knockdown phenocopies this and also suppresses the FAK/AKT pathway. ZYX knockdown inhibits the growth-promoting effect of ITGB1 overexpression, while ZYX knockdown has no effect on ITGB1 expression, placing ZYX downstream of ITGB1 in the ITGB1/ZYX/FAK/AKT axis governing EMT and apoptosis.\",\n      \"method\": \"siRNA knockdown; overexpression rescue; in vivo xenograft model; Western blot for pathway components\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by knockdown/overexpression with pathway readout, single lab\",\n      \"pmids\": [\"39143566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zyxin restricts viral envelope fusion and entry broadly across multiple virus families (HSV-1, PRV, paramyxovirus, rhabdovirus). Zyxin-KO cells show enhanced cell-cell fusion and larger viral plaques. Bulk RNA-seq of zyxin-KO cells identified altered expression of genes related to membrane potential, extracellular matrix organization, and MAPK cascade regulation, suggesting zyxin influences membrane properties relevant to viral fusion.\",\n      \"method\": \"CRISPR/Cas9 knockout; quantitative cell-cell fusion assay; plaque assay; bulk RNA-seq\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple virus families tested and quantitative fusion assay; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zyxin and VASP cooperate to assemble dense, uniformly polar actin bundles at focal adhesions with barbed ends oriented toward the cell edge. CRISPR/Cas9 knockout of zyxin and/or VASP alters FA morphology and dynamics. Cryo-ET resolves the polarity of actin filaments at FAs; the tropomyosin-decorated dorsal actin layer is unaffected by zyxin/VASP loss, revealing layered FA architecture.\",\n      \"method\": \"CRISPR/Cas9 knockout; cryo-electron tomography; live-cell imaging of FA dynamics\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-ET structural analysis combined with genetic KO, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAD51-AS1 lncRNA activates ZYX transcription via the HNRNPC/RARA axis in prostate cancer cells. RAD51-AS1 recruits HNRNPC to bind pre-RARA mRNA, positively modulating RARA expression; RARA in turn activates ZYX transcription. This pathway suppresses PCa cell migration and invasion, and rescue assays confirm RAD51-AS1 acts through ZYX.\",\n      \"method\": \"RT-qPCR; RIP/RNA binding assays; transcription reporter/ChIP-type analysis; knockdown/overexpression rescue assays; functional migration/invasion assays\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis established by rescue assay with multiple molecular mechanism assays, single lab\",\n      \"pmids\": [\"41134509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Coumestrol (CMS) binds ZYX directly (molecular docking supported by cell biology), down-regulates ZYX expression, and reduces TGF-β/SMAD pathway activity, thereby inhibiting ferroptosis in pancreatic acinar cells. ZYX overexpression counteracts the inhibitory effects of CMS on TGF-β/SMAD signaling and ferroptosis, placing ZYX upstream of TGF-β/SMAD in acinar cell ferroptosis.\",\n      \"method\": \"Molecular docking; WGCNA/network pharmacology; ZYX overexpression epistasis; in vivo caerulein-induced AP mouse model; ferroptosis assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — molecular docking is computational; functional epistasis (ZYX OE rescue) provides some experimental support but limited orthogonal mechanistic validation, single lab\",\n      \"pmids\": [\"40414075\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Zyxin (ZYX) is a LIM-domain focal adhesion adaptor that bridges integrin-based adhesion receptors with the actin cytoskeleton; it localizes dynamically to focal adhesions, stress fibers, and (in muscle/nematode) dense bodies/Z-discs, where—together with VASP—it assembles uniformly polar actin bundles, stabilizes junctional and synaptic actin networks under mechanical tension, and transduces force signals via a zyxin–14-3-3β–YAP axis to drive inflammatory gene expression; it also acts as a broad antiviral factor antagonizing envelope fusion, and functions as a transcriptionally regulated node (upstream of STMN1, downstream of ITGB1) in cancer cell invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Zyxin (ZYX) is a LIM-domain cytoskeletal adaptor that localizes to mechanically loaded adhesion structures and stabilizes actin networks under tension, while also shuttling to the nucleus to couple mechanical input to gene expression [#2, #6]. At focal adhesions it cooperates with VASP to assemble dense, uniformly polar actin bundles whose barbed ends orient toward the cell edge, defining a distinct layer of focal-adhesion architecture [#10]. In striated muscle its orthologue ZYX-1 concentrates at dense bodies/Z-discs and M-lines through interactions with \\u03b1-actinin (ATN-1), vinculin (DEB-1), and the dystrophin-associated protein DYC-1, with localization dependent on \\u03b1-actinin [#1, #2]. Its tension-sensitive recruitment stabilizes junctional and synaptic F-actin against mechanical force during morphogenesis and at mechanosensory synapses, a function residing in the C-terminal LIM domains [#3, #6]. Under oscillatory shear stress, endothelial zyxin acts as a mechanosensor that binds 14-3-3\\u03b2 to inhibit YAP Ser127 phosphorylation, promoting nuclear YAP translocation and inflammatory gene expression that drives atherosclerosis [#7]. Zyxin is embedded in cancer signaling as a transcriptionally regulated node acting downstream of ITGB1 through the FAK/AKT axis and upstream of STMN1 in tumor cell invasion [#4, #8]. It also broadly restricts viral envelope fusion and entry across multiple virus families [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first molecular partners of a zyxin orthologue, linking the LIM-domain protein ZYX-1 to germline RNA helicases and hinting at functions beyond adhesion.\",\n      \"evidence\": \"Yeast two-hybrid screen and GST pull-down in C. elegans\",\n      \"pmids\": [\"12435362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the GLH interaction not defined\", \"Relevance to vertebrate zyxin unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed ZYX-1 at the sarcomeric adhesion structure by mapping a short DYC-1 sequence sufficient for dense-body targeting, connecting zyxin to dystrophin-associated muscle architecture.\",\n      \"evidence\": \"Yeast two-hybrid, immunolocalization, and domain mapping in C. elegans muscle\",\n      \"pmids\": [\"18094057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanical or signaling role at dense bodies not tested\", \"No vertebrate confirmation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined ZYX-1 as a dynamic, peripherally associated component of muscle dense bodies and Z-discs that depends on \\u03b1-actinin and shuttles to the nucleus, suggesting a mechanotransduction role.\",\n      \"evidence\": \"Yeast two-hybrid, live imaging, FRAP, and isoform-specific genetics in C. elegans\",\n      \"pmids\": [\"23427270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets of shuttled ZYX-1 unidentified\", \"Mechanism distinguishing the two isoforms incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that zyxin stabilizes mechanosensory synapses against locomotion-induced force and localized this activity to the C-terminal LIM domains, separating force-stabilization from actin/\\u03b1-actinin binding.\",\n      \"evidence\": \"Loss-of-function genetics, epistasis, and isoform rescue in C. elegans\",\n      \"pmids\": [\"25252943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners of the LIM domains at synapses not identified\", \"How LIM domains sense force not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified ZYX as a pro-invasive node in cancer, placing it upstream of STMN1 and demonstrating a tumor-suppressive ZYX-derived peptide that engages TSP1, revealing both full-length and fragment-level functions.\",\n      \"evidence\": \"Knockdown/overexpression with RNA-seq, proteomics, and rescue in glioblastoma; peptide pull-down and functional assays in ovarian cancer\",\n      \"pmids\": [\"31949244\", \"32953725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ZYX regulates STMN1 levels unknown\", \"Physiological relevance of ZYX36-58 peptide unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated tension-dependent recruitment of zyxin to apical junctions and stress-fiber strain sites, establishing it as part of a force-sensitive system stabilizing junctional actin during morphogenesis.\",\n      \"evidence\": \"C. elegans genetics, imaging, epistasis with cadherin/catenin hypomorphs, and vertebrate stress-fiber strain-site recruitment assay\",\n      \"pmids\": [\"36384139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The force-sensing element within zyxin not molecularly defined\", \"Link between junctional and focal-adhesion roles unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected zyxin mechanosensing to transcription by showing it binds 14-3-3\\u03b2 to relieve YAP Ser127 phosphorylation, driving nuclear YAP and endothelial inflammation in atherosclerosis.\",\n      \"evidence\": \"Endothelial-specific knockout ApoE\\u2212/\\u2212 mouse, disturbed-flow system, and co-IP/phosphorylation studies (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct binding of zyxin to 14-3-3\\u03b2 versus indirect effect not fully distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Positioned ZYX within the ITGB1/FAK/AKT signaling axis, showing it acts downstream of integrin \\u03b21 to drive EMT and suppress apoptosis in hepatocellular carcinoma.\",\n      \"evidence\": \"siRNA knockdown, overexpression rescue, xenograft, and pathway Western blots\",\n      \"pmids\": [\"39143566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between ZYX and FAK/AKT not shown\", \"Whether effect requires zyxin's cytoskeletal localization untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural output of zyxin-VASP cooperation at focal adhesions, showing assembly of uniformly polar actin bundles and a layered focal-adhesion architecture.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, cryo-electron tomography, and live-cell imaging (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Order of zyxin and VASP recruitment to nascent bundles unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an unexpected broad antiviral function in which zyxin restricts viral envelope fusion and entry, potentially via effects on membrane properties.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, cell-cell fusion and plaque assays, and bulk RNA-seq (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct molecular mechanism linking zyxin to membrane fusion undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ZYX's regulatory range as a transcriptionally controlled node, identifying lncRNA/HNRNPC/RARA-driven activation of ZYX that suppresses prostate cancer invasion and a TGF-\\u03b2/SMAD-coupled role in acinar cell ferroptosis.\",\n      \"evidence\": \"RIP, reporter/ChIP-type analysis, and rescue in prostate cancer; molecular docking and overexpression epistasis in a pancreatitis mouse model\",\n      \"pmids\": [\"41134509\", \"40414075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ferroptosis link rests partly on computational docking\", \"Apparently opposite invasion effects across cancer contexts unreconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How zyxin's mechanosensitive LIM domains physically sense force and how this single adaptor coordinates its adhesion, transcriptional, antiviral, and context-dependent cancer roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of force-induced conformational change\", \"Unifying mechanism across diverse functions not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 6, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [\n      \"focal adhesion\",\n      \"dense body/Z-disc\"\n    ],\n    \"partners\": [\n      \"VASP\",\n      \"ATN-1/alpha-actinin\",\n      \"DEB-1/vinculin\",\n      \"DYC-1\",\n      \"14-3-3beta\",\n      \"YAP\",\n      \"GLH\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"ZYX","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"uncited_synthesis","uniprot_band":"medium","rules_fired":"R8","issue":"R8: 3/7 claims uncited (43%)"},"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}